New research from France has shown why ketamine, the infamous party drug and horse tranquiliser, may be so rapid and effective in providing relief for severe depression.
Approximately one-third of patients with depression do not respond to conventional antidepressant treatments and over the last decade, ketamine, an ionotropic glutamatergic N-methyl-d-aspartate receptor antagonist, has become a novel therapy for treatment resistant depression (TRD).
The study, published 28 September 2022 in JAMA Psychiatry, found that ketamine not only helped people with depression to focus on positive information rather than negative news, but it also made people update their beliefs based on that positive information – with increasing frequency.
In as little as four hours after their first ketamine infusion, participants updated their beliefs more often after good news, rather than bad news, relative to baseline and sequential testing in healthy controls, with similar effects seen when comparing the effect on belief updating up to one week after treatment.
Lead author, Dr Liane Schmidt from the Paris Brain Institute, explained that even though several clinical trials have shown that ketamine has a rapid antidepressant effect that peaks within 24 hours, little was known about the cognitive effects of ketamine in TRD and their link to clinical improvement.
“Cognitive models of depression propose that maladaptive beliefs bias the perception and interpretation of life events and produce a negative view of oneself, the world, and the future,” Dr Schmidt explained.
“Importantly, patients with depression have been shown to lack an optimism bias in belief updating and to hold persistently negative expectations about the future, despite contradictory evidence.
“This phenomenon has also been referred to as pervasive pessimism and stands in stark contrast to the unrealistic optimism that is frequently observed in healthy individuals,” she said.
“These characteristics are thought to play an important role in the maintenance of depressive symptoms and, potentially, in treatment resistance. However, it was unknown how ketamine affects the mechanisms of belief updating in patients with TRD, which are potentially key to understanding its antidepressant effects.
“Here, we asked (1) whether and through what computational mechanisms ketamine restores optimism biases in belief updating and (2) how such potential cognitive effects link to antidepressant effects.”
In total, 26 patients with TRD (defined by the failure to respond to at least 2 antidepressant treatments) and 30 healthy control participants between 18 and 70 years were enrolled in the study, a sample size consistent with prior studies investigating ‘belief updating’ in patients with depression.
Those with TRD were given three doses of ketamine on different occasions, and all participants performed a belief-updating task adapted from decision neuroscience, involving two sessions of 40 trials.
If the first session, participants were asked on a trial-by-trial basis to estimate their lifetime likelihood of experiencing varying adverse life events (i.e., the initial estimate) and the likelihood of someone else with a similar socioeconomic background experiencing a given event – the estimated base rate.
At the end of each trial, participants were told the actual base rate of events in the general population: if the base rate was smaller than the participant’s initial estimate, the trial was categorized as a good news trial; if the actual base rate was greater than the participant’s initial estimate, the trial was categorized as a bad news trial.
The participant’s attention was not explicitly drawn to this good news/bad news categorization of the trials and importantly, the same 40 adverse life events were presented again in session two, where participants re-estimated their lifetime risk, considering the base rate.
“The results showed, in line with previous studies, that ketamine induced a rapid and sustained decrease in depressive symptoms,” Dr Schmidt said.
“On the cognitive level, patients with TRD showed weaker optimism biases in belief updating at baseline, compared with 4 hours after the first ketamine infusion, with the significant increase in optimism bias and correlating reduction in depressive symptoms after one week of treatment formally mediating the clinical effect.
“In conclusion, our results converge toward the finding that ketamine improves TRD, and that this improvement is associated with changes in the belief-updating processes underpinned by increased asymmetric learning from positive rather than negative estimation errors.
“These findings shed light on the possible mechanisms underlying ketamine’s rapid antidepressant effects and pave the way toward the use of ketamine-augmented psychotherapy protocols.”